Islet cell transplantation can lead to insulin independence, reduced hypoglycemia, and amelioration of diabetes complications in patients with type 1 diabetes. The systemic delivery of anti‐inflammatory agents, while considered crucial to limit the early loss of islets associated with intrahepatic infusion, increases the burden of immunosuppression. In an effort to decrease the pharmaceutical load to the patient, we modified the pancreatic islet surface with long‐chain poly(ethylene glycol) (PEG) to mitigate detrimental host‐implant interactions. The effect of PEGylation on islet engraftment and long‐term survival was examined in a robust nonhuman primate model via three paired transplants of dosages 4300, 8300, and 10 000 islet equivalents per kg body weight. A reduced immunosuppressive regimen of anti‐thymocyte globulin induction plus tacrolimus in the first posttransplant month followed by maintenance with sirolimus monotherapy was employed. To limit transplant variability, two of the three pairs were closely MHC‐matched recipients and received MHC‐disparate PEGylated or untreated islets isolated from the same donors. Recipients of PEGylated islets exhibited significantly improved early c‐peptide levels, reduced exogenous insulin requirements, and superior glycemic control, as compared to recipients of untreated islets. These results indicate that this simple islet modification procedure may improve islet engraftment and survival in the setting of reduced immunosuppression.

Mesenchymal stem cells (MSC) have been shown to be immunomodulatory, tissue regenerative, and graft promoting; however, several questions remain with regard to ideal MSC source and timing of administration. In this study, we utilized a rigorous preclinical model of allogeneic islet cell transplantation, incorporating reduced immune suppression and near to complete mismatch of major histocompatibility antigens between the diabetic cynomolgus monkey recipient and the islet donor, to evaluate both the graft promoting impact of MSC source, that is, derived from the islet recipient, the islet donor or an unrelated third party as well as the impact of timing. Co-transplant of MSC and islets on post-operative day 0, followed by additional IV MSC infusions in the first posttransplant month, resulted in prolongation of rejection free and overall islet survival and superior metabolic control for animals treated with recipient as compared to donor or third-party MSC. Immunological analyses demonstrated that infusion of MSC from either source did not prevent alloantibody formation to the islet or MSC donor; however, treatment with recipient MSC resulted in significant downregulation of memory T cells, decreased antidonor T cell proliferation, and a trend toward increased Tregulatory:Tconventional ratios.

Polyethylene glycol (PEG)–based conformal coating (CC) encapsulation of transplanted islets is a promising β cell replacement therapy for the treatment of type 1 diabetes without chronic immunosuppression because it minimizes capsule thickness, graft volume, and insulin secretion delay. However, we show here that our original CC method, the direct method, requiring exposure of islets to low pH levels and inclusion of viscosity enhancers during coating, severely affected the viability, scalability, and biocompatibility of CC islets in nonhuman primate preclinical models of type 1 diabetes. We therefore developed and validated in vitro and in vivo, in several small- and large-animal models of type 1 diabetes, an augmented CC method—emulsion method—that achieves hydrogel CCs around islets at physiological pH for improved cytocompatibility, with PEG hydrogels for increased biocompatibility and with fivefold increase in encapsulation throughput for enhanced scalability.

Gut microbiota (GM) in the epigenetic mechanisms of diabetes mellitus and the reprogramming of the cells is a novel and emerging concept. The purpose of this chapter is to describe the modification of the GM and its relation with DM2. The increased risk of this disease is associated with changes in the amount of Bacteroides/Clostridium in the Firmicutes/Bacteroidetes ratio of people having DM. A dysbiosis state associated generates low-grade inflammation with similar characteristics that occur under metabolic syndrome, whose pattern is recognized by Toll-like receptor that recognizes important patterns of immunity. The synthesis of butyrate generated by intestinal microorganisms inhibits the metabolic pathway of histone deacetylase, promoting cellular differentiation, proliferation, and insulin resistance. On the other hand, the direct relationship between the neuroendocrine system and the GM has been demonstrated through the production of serotonin by enterochromaffin cells, whose action could influence the etiopathogenic factors of DM2.

The scientific literature has shown that diet is able to modify the gut microbiota and contribute to obesity and diabetes development. This process-characterized by inflammation and gut barrier disruption-can affect the immune system and alter the adipogenesis and insulin resistance. This chapter describes the advances in nutrigenomics and Human Intestinal Microbiota (HIM) modification, and its relation with diabetes mellitus type two (DM2). In context where health and feeding are the main concerns of the human being, food innovation takes a special interest to people that look for a healthy diet or demand a functional aliments, such as nutraceutical. Some products derived from diet and interaction with HIM module the expression of many genes on the host, the so-called epigenome, with favorable effects. Novel functional fiber like low-glycemic oligosaccharides and sweeteners shows a potential prebiotic activity giving a new focus of nutritional guidelines for control and prevention of DM2. The use of prebiotics derived from functional fiber sources, such as fructo-oligosaccharides and beta-glucans as well as lignin and keffir, can contribute to the development of a healthy HIM by promoting the growth of specific bacteria, some of them associated with the prevention of obesity and diabetes.